Dorsal raphe neuroinflammation promotes dramatic behavioral stress dysregulation.

Impulsivity, risk-taking behavior, and elevated stress responsivity are
prominent symptoms of mania, a behavioral state common to schizophrenia
and bipolar disorder. Though inflammatory processes activated within the
brain are involved in the pathophysiology of both disorders, the
specific mechanisms by which neuroinflammation drives manic behavior are
not well understood. Serotonin cell bodies originating within the
dorsal raphe (DR) play a major role in the regulation of behavioral
features characteristic of mania. Therefore, we hypothesized that the
link between neuroinflammation and manic behavior may be mediated by
actions on serotonergic neurocircuitry. To examine this, we induced
local neuroinflammation in the DR by viral delivery of Cre recombinase
into interleukin (IL)-1β(XAT) transgenic male and female mice, resulting
in overexpressing of the proinflammatory cytokine, IL-1β. For assertion
of brain-region specificity of these outcomes, the prefrontal cortex
(PFC), as a downstream target of DR serotonergic projections, was also
infused. Inflammation within the DR, but not the PFC, resulted in a
profound display of manic-like behavior, characterized by increased
stress-induced locomotion and responsivity, and reduced
risk-aversion/fearfulness. Microarray analysis of the DR revealed a
dramatic increase in immune-related genes, and dysregulation of genes
important in GABAergic, glutamatergic, and serotonergic
neurotransmission. Behavioral and physiological changes were driven by a
loss of serotonergic neurons and reduced output as measured by
high-performance liquid chromatography, demonstrating
inflammation-induced serotonergic hypofunction. Behavioral changes were
rescued by acute selective serotonin reuptake inhibitor treatment,
supporting the hypothesis that serotonin dysregulation stemming from
neuroinflammation in the DR underlies manic-like behaviors.

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